Stroke: Symptoms and Prevention

1. Introduction

Stroke represents a critical cerebrovascular event characterized by the acute onset of neurological deficit due to focal injury of the central nervous system. It constitutes a leading cause of mortality and long-term adult disability globally, imposing a substantial burden on healthcare systems. The clinical and pharmacological management of stroke is predicated on a fundamental understanding of its pathophysiology, the rapid recognition of its symptoms, and the rigorous application of evidence-based preventive strategies.

The historical conceptualization of stroke has evolved significantly. Ancient descriptions, such as those in Hippocratic writings, referred to apoplexy. The modern understanding began to crystallize in the 17th century with Johann Jacob Wepfer’s identification of intracranial hemorrhage as a cause, and later with the development of vascular anatomy and physiology. The 20th century witnessed pivotal advances, including the widespread adoption of computed tomography (CT) imaging, which allowed for the definitive differentiation between ischemic and hemorrhagic subtypes, and the establishment of thrombolytic therapy.

For pharmacology and medicine, stroke is a paradigm of acute neurological therapeutics and chronic vascular risk management. It integrates principles of hemodynamics, coagulation, neuronal metabolism, and secondary neurodegeneration. The pharmacotherapeutic approach spans acute revascularization, neuroprotection, and long-term prevention targeting modifiable risk factors.

Learning Objectives

• Differentiate the pathophysiological mechanisms underlying ischemic stroke, hemorrhagic stroke, and transient ischemic attack (TIA).
• Recognize and interpret the clinical symptoms of stroke using standardized assessment tools such as the FAST mnemonic and the NIH Stroke Scale.
• Evaluate the evidence for primary and secondary preventive strategies, including pharmacological interventions such as antiplatelet agents, anticoagulants, antihypertensives, and lipid-lowering therapies.
• Analyze the role of non-pharmacological interventions, including lifestyle modification and surgical procedures, in comprehensive stroke prevention.
• Apply knowledge of stroke syndromes to clinical case scenarios to formulate appropriate diagnostic and management plans.

2. Fundamental Principles

The foundational principles of stroke medicine are built upon precise definitions, an understanding of cerebral circulation, and the metabolic vulnerability of neural tissue.

Core Concepts and Definitions

Stroke is defined by the World Health Organization as rapidly developing clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than of vascular origin. This definition is clinically operational.

Ischemic Stroke accounts for approximately 85% of cases and results from occlusion of a cerebral artery, leading to focal cerebral ischemia and infarction. The core infarct is surrounded by the ischemic penumbra, a region of hypoperfused, functionally impaired but potentially salvageable tissue.

Hemorrhagic Stroke includes intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), resulting from rupture of a cerebral vessel. ICH involves bleeding directly into the brain parenchyma, while SAH involves bleeding into the subarachnoid space.

Transient Ischemic Attack (TIA) was historically defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. The modern tissue-based definition classifies TIA as a transient episode with no radiographic evidence of infarction, emphasizing it as a medical emergency and a powerful warning sign of impending stroke.

Theoretical Foundations

The theoretical underpinning of ischemic stroke is the concept of the ischemic cascade. Following arterial occlusion, cerebral blood flow (CBF) drops below critical thresholds. At CBF below 20 mL/100g/min, neuronal electrical failure occurs; below 10 mL/100g/min, membrane pump failure leads to ionic imbalance, cytotoxic edema, and ultimately cell death. This cascade involves excitotoxicity, oxidative stress, inflammation, and apoptosis.

Cerebral autoregulation maintains constant CBF across a range of mean arterial pressures (typically 60-150 mm Hg). This autoregulation is often impaired in chronic hypertension and acutely after stroke, making the brain more vulnerable to perfusion pressure changes.

For hemorrhagic stroke, the mass effect from the hematoma and surrounding edema is a key theoretical concern, causing increased intracranial pressure, tissue displacement, and herniation.

Key Terminology

• Penumbra: The ischemic but potentially viable tissue surrounding the core infarct.
• Atrial Fibrillation (AF): A cardiac arrhythmia and major risk factor for cardioembolic stroke.
• Atherosclerosis: A disease of large and medium arteries characterized by plaque formation, a principal cause of large vessel ischemic stroke.
• Lipohyalinosis: Pathological thickening of small penetrating cerebral arteries, associated with hypertension and causing lacunar strokes.
• Thrombolysis: The pharmacological dissolution of an occlusive thrombus.
• Secondary Prevention: Interventions to prevent recurrent stroke after an initial event or TIA.

3. Detailed Explanation

A comprehensive understanding of stroke requires in-depth exploration of etiology, symptomatology, and the multifactorial nature of prevention.

Pathophysiological Mechanisms

Ischemic stroke mechanisms are broadly categorized by the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification:

1. Large Artery Atherosclerosis: Thrombosis or artery-to-artery embolism originating from atherosclerotic plaques in extracranial (e.g., carotid bifurcation) or large intracranial arteries.
2. Cardioembolism: Embolism of cardiac origin, commonly from atrial fibrillation, valvular disease, ventricular thrombus post-myocardial infarction, or patent foramen ovale.
3. Small Vessel Occlusion (Lacunar): Occlusion of small penetrating arteries, typically due to lipohyalinosis or microatheroma, leading to small, deep infarcts.
4. Stroke of Other Determined Etiology: Includes rare causes such as arterial dissection, vasculitis, hypercoagulable states, or genetic disorders like CADASIL.
5. Stroke of Undetermined Etiology: Includes cryptogenic strokes where no cause is identified despite extensive investigation.

Hemorrhagic stroke pathophysiology differs. Intracerebral hemorrhage most commonly results from the rupture of small vessels damaged by chronic hypertension or cerebral amyloid angiopathy. Subarachnoid hemorrhage is most frequently caused by the rupture of a saccular (berry) aneurysm.

Symptoms and Clinical Presentation

Symptoms are sudden in onset and reflect the vascular territory affected. Recognition is aided by public awareness campaigns such as FAST (Face, Arms, Speech, Time). A more detailed clinical assessment includes:

• Anterior Circulation (Carotid) Symptoms: Contralateral hemiparesis/hemisensory loss (face and arm > leg), contralateral homonymous hemianopia, aphasia (dominant hemisphere), or neglect/visuospatial dysfunction (non-dominant hemisphere).
• Posterior Circulation (Vertebrobasilar) Symptoms: Vertigo, diplopia, dysphagia, dysarthria, ataxia, crossed signs (ipsilateral cranial nerve deficit with contralateral motor/sensory deficit), and cortical blindness.
• Lacunar Syndrome Patterns: Pure motor stroke, pure sensory stroke, sensorimotor stroke, ataxic hemiparesis, and dysarthria-clumsy hand syndrome.

The severity is often quantified using the National Institutes of Health Stroke Scale (NIHSS), a 15-item neurological examination scale that assesses level of consciousness, visual function, motor strength, sensation, language, and inattention.

Prevention: A Multifactorial Approach

Stroke prevention is stratified into primary prevention (preventing a first-ever stroke in at-risk individuals) and secondary prevention (preventing recurrence after a TIA or stroke). The approach is multifactorial, targeting modifiable risk factors.

Non-Modifiable and Modifiable Risk Factors

Pharmacological Prevention Strategies

The cornerstone of pharmacological prevention involves antithrombotic therapy, blood pressure control, and lipid management.

Antiplatelet Agents: First-line for non-cardioembolic ischemic stroke/TIA prevention.

• Aspirin: Inhibits cyclooxygenase-1, reducing thromboxane A₂-mediated platelet aggregation. Typical dose for prevention is 75-100 mg daily.
• Clopidogrel: An irreversible P2Y₁₂ adenosine diphosphate (ADP) receptor antagonist. Often used in patients with aspirin intolerance or higher risk profiles.
• Dual Antiplatelet Therapy (DAPT): The combination of aspirin and clopidogrel for a short duration (e.g., 21-90 days) may be considered for high-risk TIA or minor stroke, but long-term use is associated with increased bleeding risk.

Anticoagulants: First-line for stroke prevention in atrial fibrillation and other cardioembolic sources.

• Vitamin K Antagonists (e.g., Warfarin): Requires regular monitoring (INR target typically 2.0-3.0) and is influenced by diet and drug interactions.
• Direct Oral Anticoagulants (DOACs): Include dabigatran (direct thrombin inhibitor), and rivaroxaban, apixaban, edoxaban (Factor Xa inhibitors). Generally preferred over warfarin for non-valvular AF due to more predictable pharmacokinetics, fewer drug interactions, and comparable or superior efficacy and safety profiles.

Antihypertensive Agents: Blood pressure reduction is arguably the most effective single intervention for both primary and secondary stroke prevention. A reduction of approximately 10 mm Hg systolic and 5 mm Hg diastolic is associated with a one-third reduction in stroke risk. All major classes (ACE inhibitors, ARBs, diuretics, calcium channel blockers) are effective, with the choice often guided by comorbidities.

Lipid-Lowering Agents: Statins (HMG-CoA reductase inhibitors) are central. Beyond lowering LDL-C, they possess pleiotropic effects including plaque stabilization and anti-inflammatory activity. High-intensity statin therapy (e.g., atorvastatin 40-80 mg daily) is recommended for secondary prevention after atherosclerotic stroke.

Non-Pharmacological and Interventional Prevention

• Carotid Endarterectomy (CEA) or Carotid Artery Stenting (CAS): Considered for symptomatic patients with 70-99% carotid stenosis. For asymptomatic stenosis, the benefit is more marginal and must be weighed against procedural risk.
• Left Atrial Appendage Occlusion (LAAO): A procedural option for stroke prevention in patients with non-valvular AF who have contraindications to long-term anticoagulation.
• Lifestyle Modifications: Smoking cessation, dietary modifications (e.g., DASH or Mediterranean diet), regular physical activity, weight management, and moderate alcohol consumption constitute essential components of a holistic prevention strategy.

4. Clinical Significance

The clinical significance of stroke knowledge is profound, directly impacting diagnostic acuity, therapeutic decision-making, and long-term patient outcomes.

Relevance to Drug Therapy

Pharmacotherapy for stroke is time-sensitive and subtype-specific. In acute ischemic stroke, intravenous alteplase (recombinant tissue plasminogen activator, rt-PA) must be administered within 4.5 hours of symptom onset, with earlier treatment yielding greater benefit. Its use is contraindicated in hemorrhagic stroke, underscoring the critical need for rapid neuroimaging. Endovascular thrombectomy has emerged as a standard of care for large vessel occlusions, extending the treatment window up to 24 hours in selected patients based on advanced imaging.

For secondary prevention, drug therapy is tailored to stroke etiology. The incorrect assignment of an anticoagulant for a patient with lacunar stroke (a non-cardioembolic subtype) would expose them to unnecessary bleeding risk without proven benefit. Conversely, withholding anticoagulation in a patient with AF and prior stroke significantly increases the risk of devastating recurrence.

Practical Applications in Risk Assessment

Stratification tools are used clinically to guide preventive therapy. The CHA₂DS₂-VASc score estimates stroke risk in atrial fibrillation, guiding the initiation of anticoagulation. The HAS-BLED score estimates bleeding risk on anticoagulants, prompting modifiable risk factor correction rather than absolute denial of therapy. For asymptomatic individuals, tools like the Framingham Stroke Risk Profile incorporate multiple risk factors to estimate 10-year probability, informing the intensity of primary prevention efforts.

Clinical Examples of Pharmacological Impact

The clinical impact of preventive pharmacology is evidenced by population studies. The widespread use of antihypertensives is credited with a significant portion of the documented decline in stroke incidence and mortality over recent decades. The introduction of statins has further reduced the risk of atherosclerotic stroke. The paradigm shift from warfarin to DOACs for AF has simplified management and improved adherence, potentially increasing the proportion of at-risk patients receiving effective prophylaxis.

5. Clinical Applications and Examples

The application of principles is best illustrated through clinical scenarios that require synthesis of knowledge regarding symptoms, pathophysiology, and prevention.

Case Scenario 1: Acute Presentation and Etiologic Workup

A 68-year-old male with a history of hypertension and smoking presents with acute onset of right-sided facial droop, arm weakness, and slurred speech lasting 90 minutes. NIHSS score is 6. Non-contrast head CT shows no hemorrhage. He receives intravenous alteplase. Subsequent MRI reveals an acute infarct in the left frontal lobe. Carotid ultrasound shows 80% stenosis of the left internal carotid artery. Echocardiogram and rhythm monitoring show no cardioembolic source.

Analysis and Application: The symptoms localize to the left middle cerebral artery territory. The absence of hemorrhage allowed for safe thrombolysis. The identification of significant ipsilateral carotid stenosis establishes the likely etiology as large artery atherosclerosis. Secondary prevention would involve:

• Initiation of high-intensity statin therapy (e.g., atorvastatin 80 mg daily) and antiplatelet therapy (e.g., clopidogrel 75 mg daily or aspirin 81 mg daily).
• Referral for carotid revascularization (CEA or CAS) given symptomatic high-grade stenosis.
• Aggressive blood pressure control and smoking cessation counseling.
• Dual antiplatelet therapy might be considered for the first 21-90 days post-event given the symptomatic stenosis, followed by single agent therapy long-term.

Case Scenario 2: Prevention in Atrial Fibrillation

A 72-year-old female with a history of paroxysmal atrial fibrillation, hypertension, and diabetes (CHA₂DS₂-VASc score = 4) presents for a routine check-up. She is currently on aspirin 81 mg daily. Her blood pressure is 145/88 mm Hg.

Analysis and Application: This scenario highlights a common primary prevention gap. Aspirin provides minimal protection against cardioembolic stroke in AF and is not recommended as monotherapy. A CHA₂DS₂-VASc score of 4 (1 point each for age, hypertension, diabetes; 2 points for female sex) indicates a high annual stroke risk, warranting oral anticoagulation. Management steps would include:

• Discontinuation of aspirin for stroke prevention in AF.
• Initiation of a DOAC (e.g., apixaban, rivaroxaban, dabigatran, or edoxaban) given their favorable risk-benefit profile compared to warfarin.
• Titration of antihypertensive therapy to achieve a target blood pressure of <130/80 mm Hg.
• Assessment of bleeding risk using HAS-BLED, with attention to correcting modifiable factors like uncontrolled hypertension.

Case Scenario 3: Lacunar Stroke and Risk Factor Management

A 60-year-old male presents with a sudden onset of pure right-sided weakness, affecting the face, arm, and leg equally, with no sensory, visual, or language deficits. Symptoms persist. MRI confirms a small, deep infarct in the left internal capsule. Diagnostic workup reveals no carotid stenosis or cardiac embolic source. He has untreated hypertension (BP 160/100) and an LDL-C of 3.5 mmol/L.

Analysis and Application: The pure motor deficit is classic for a lacunar stroke, implicating small vessel disease, most commonly due to hypertensive arteriolosclerosis. Preventive strategy focuses intensely on risk factor control:

• Initiation of a single antiplatelet agent (e.g., clopidogrel or aspirin). Dual therapy is not indicated long-term for this etiology.
• Aggressive blood pressure lowering is paramount. An ACE inhibitor or ARB may be preferred due to potential specific benefits on cerebral small vessels.
• Initiation of a statin to lower LDL-C, with a target of 50% reduction from baseline.
• Lifestyle counseling regarding diet, sodium restriction, and exercise.

6. Summary and Key Points

Stroke represents a major public health challenge where knowledge of symptoms and prevention is directly linked to improved patient outcomes.

Summary of Main Concepts

• Stroke is broadly categorized into ischemic (85%) and hemorrhagic subtypes, each with distinct pathophysiology, requiring different acute management strategies.
• Rapid recognition of stroke symptoms using tools like FAST is critical for timely intervention, as the efficacy of acute treatments like thrombolysis and thrombectomy is highly time-dependent.
• Transient ischemic attack is a neurological emergency and a critical opportunity for intervention to prevent a major stroke.
• Stroke prevention is etiology-specific and multifactorial, integrating strict control of vascular risk factors (hypertension, diabetes, dyslipidemia), lifestyle modification, and appropriate antithrombotic therapy.
• The choice of antithrombotic agent is guided by stroke mechanism: antiplatelets for non-cardioembolic stroke and anticoagulants for cardioembolic stroke (primarily atrial fibrillation).

Clinical Pearls

• “Time is brain”: Approximately 1.9 million neurons are lost each minute during an acute ischemic stroke.
• Blood pressure management is the cornerstone of both primary and secondary prevention for all stroke subtypes, including hemorrhagic stroke.
• In atrial fibrillation, the CHA₂DS₂-VASc score should guide anticoagulation; aspirin monotherapy is inadequate for stroke prevention in most patients with AF.
• For secondary prevention after atherosclerotic stroke, high-intensity statin therapy is recommended regardless of baseline LDL-C level.
• A patient with TIA or minor stroke from large artery atherosclerosis (e.g., symptomatic carotid stenosis) may benefit from short-term dual antiplatelet therapy, but the duration must be limited to mitigate bleeding risk.

References

1. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.